tbuckley/cabot-search huggingface dataset:
Hypermitotic meningiomas harbor DNA methylation subgroups with distinct biological and clinical features
Authors: Abrar Choudhury, William C Chen, Calixto-Hope G Lucas, James C Bayley, Akdes S Harmanci, Sybren L N Maas, Sandro Santagata, Tiemo Klisch, Arie Perry, Wenya Linda Bi, Felix Sahm, Akash J Patel, Stephen T Magill, David R Raleigh
Journal: Neuro-Oncology (2022)

Meningiomas, the most common primary intracranial tumors, can be separated into 3 DNA methylation groups with distinct biological drivers, clinical outcomes, and therapeutic vulnerabilities. Alternative meningioma grouping schemes using copy number variants, gene expression profiles, somatic short variants, or integrated molecular models have been proposed. These data suggest meningioma DNA methylation groups may harbor subgroups unifying contrasting theories of meningioma biology.A total of 565 meningioma DNA methylation profiles from patients with comprehensive clinical follow-up at independent discovery (n = 200) or validation (n = 365) institutions were reanalyzed and classified into Merlin-intact, Immune-enriched, or Hypermitotic DNA methylation groups. RNA sequencing from the discovery (n = 200) or validation (n = 302) cohort were analyzed in the context of DNA methylation groups to identify subgroups. Biological features and clinical outcomes were analyzed across meningioma grouping schemes.RNA sequencing revealed differential enrichment of FOXM1 target genes across two subgroups of Hypermitotic meningiomas. Differential expression and ontology analyses showed the subgroup of Hypermitotic meningiomas without FOXM1 target gene enrichment was distinguished by gene expression programs driving macromolecular metabolism. Analysis of genetic, epigenetic, gene expression, or cellular features revealed Hypermitotic meningioma subgroups were concordant with Proliferative or Hypermetabolic meningiomas, which were previously reported alongside Merlin-intact and Immune-enriched tumors using an integrated molecular model. The addition of DNA methylation subgroups to clinical models refined the prediction of postoperative outcomes compared to the addition of DNA methylation groups.Meningiomas can be separated into three DNA methylation groups and Hypermitotic meningiomas can be subdivided into Proliferative and Hypermetabolic subgroups, each with distinct biological and clinical features.
LLM Abstracts for AJH V97 S3
Authors: Das Sulagna, Leonhardth Lex, Stuart Ryan, Calvo Alejandro, Wesley Tang, Akbar Shahzad, Swayze Krisalyn, Hemenway Gregory, Fu Chen, Fung Henry, Khatri Rishabh, Maruthi Rohit, Song Jun, Harcha John, L Doug, Hammad Ashley, Davi Franco, Chung Sally, Bryan Mara, Skoble Justin, Garner Elizabeth, Nesheiwat Tonia, Portella Socorro, Kanner Steven, Rizvi Syed, Essel James, Daver Naval, Liu Ke, Werneke Scott, Rustia Evelyn, Ramsingh Giri, Vyas Paresh
Journal: American Journal of Hematology (2022)

Introduction:The direct oral anticoagulants (DOACs) are the standard of care for treatment and prevention of pulmonary embolism (PE) and deep venous thrombosis (DVT), also used for stroke prevention in patients with nonvalvular atrial fibrillation.Ischemic strokes and cerebrovascular diseases often lead to symptomatic epilepsy among elderly patients, requiring addition of chronic antiepileptic drugs.The cytochrome P-450 (CYP 450) system is responsible for DOAC metabolism, while phenytoin is a well-documented CYP-450 inducer.We present a case with documented interaction between Apixaban and phenytoin, resulting in recurrent DVT.Methods: A 60-year-old male with medical history of DVT and PE status post Inferior Vena Cava (IVC) filter on warfarin anticoagulation and history of seizures on phenytoin, presented to the emergency room with lower extremity swelling and shortness of breath.On admission, he was found to have acute right profunda femoral DVT.He reported provoked left lower extremity DVT with bilateral sub massive PE after hemilaminectomy eight years prior, requiring initiation of warfarin anticoagulation.Six months ago, he was transitioned to Eliquis 5 mg twice daily.He reported compliance without missed doses.He was known to be on phenytoin for many years due to a history of seizures.The hematology service was consulted due to concern for DOAC failure.It was recognized that apixaban failure was due to phenytoin use.He was bridged via lowmolecular weight heparin to warfarin and discharged 2 days later.Results: Apixaban is metabolized by the CYP 450 system, primarily CYP3A4.It is a substrate of the efflux transporter P-glycoprotein (Pgp) which regulates the elimination of DOACs from the gastrointestinal lumen.Potent CYP3A4 and P-gp inducers like phenytoin may reduce the plasma concentration of apixaban and cause thrombosis, while potent inhibitors may increase the plasma concentration of apixaban and cause bleeding.In 2017, Hager et al. reported occurrence of left atrial thrombus due to concomitant use of phenytoin 300 mg daily and dabigatran 150 mg twice daily in a 70-year-old patient with history of recurrent DVT and PE.Similarly, Becerra et al. describe subtherapeutic DOAC (or factor Xa) levels in a 48-year-old woman with cerebral vein thrombosis also taking phenytoin.Discussion: Drug-drug interactions between AEDs and DOACs are dangerous and physicians should be aware of metabolism and safety profiles when prescribing DOAC's.Given the clear understanding of the effect of phenytoin on apixaban metabolism, it is evident that concomitant administration is contraindicated.
Haploidentical Versus Matched Sibling Donor Hematopoietic Stem Cell Transplantation for Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia: A Study From the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Authors: Arnon Nagler, Myriam Labopin, Ryszard Swoboda, Pietro Pioltelli, Mutlu Arat, Ibrahim Yakoub-Agha, Alexander Kulagin, Anna Maria Raiola, Hakan Ozdogu, Antonio Risitano, Zubeyde Nur Ozkurt, Jaime Sanz, Eolia Brissot, Peric Zina, Sebastian Giebel, Fabio Ciceri, Mohamad Mohty
Journal: HemaSphere (2022)

The results of haploidentical stem cell transplantation (haploHCT) for patients with acute lymphoblastic leukemia (ALL) transplanted in active disease remain largely unknown. We retrospectively analyzed adult patients with R/R ALL who underwent haploHCT or matched sibling donor (MSD-HCT) as a first transplantation between 2012 and 2020. The analysis comprised 274 patients, 94 had a haploHCT, and 180 had an MSD-HCT. The median follow-up was 32 months. The median age was 33 (range 18-76) and 37 (18-76) years in the haplo- and MSD-HCT groups, respectively. Post-transplant cyclophosphamide (PTCy) was used in 88% of haploHCT and in 4% of the MSD-HCT group. Graft-versus-host disease grade III-IV was higher in haploHCT than in the MSD-HCT group (18% versus 9%; P = 0.042). The 2-year chronic (c) graft-versus-host disease rates were 17% versus 33% (hazard ratio [HR] = 0.56; P = 0.14), respectively. By multivariate analysis, relapse incidence, and leukemia-free survival were not significatively different between the transplant groups, while nonrelapse mortality (NRM) was significantly higher (25% versus 18% at 2 years; HR = 2.03; P = 0.042) and overall survival (OS) lower (22% versus 38% at 2 years; HR = 1.72; P = 0.009) in the haploHCT group compared with the MSD-HCT group. We conclude that the 2-year OS of R/R ALL patients undergoing MSD transplants is significantly better than in haploHCT with a higher NRM in the latter.
Next-generation brain observatories
Authors: Christof Koch, Karel Svoboda, Amy Bernard, Michele A. Basso, Anne K. Churchland, Adrienne L. Fairhall, Peter A. Groblewski, Jérôme A. Lecoq, Zachary F. Mainen, Mackenzie W. Mathis, Shawn R. Olsen, John w. Phillips, Alexandre Pouget, Shreya Saxena, Josh H. Siegle, Anthony M. Zador
Journal: Neuron (2022)
Deep learning of cross-species single-cell landscapes identifies conserved regulatory programs underlying cell types
Authors: Jiaqi Li, Jingjing Wang, Peijing Zhang, Renying Wang, Yuqing Mei, Zhongyi Sun, Lijiang Fei, Mengmeng Jiang, Lifeng Ma, Weigao E, Haide Chen, Xinru Wang, Yuting Fu, Hanyu Wu, Daiyuan Liu, Xueyi Wang, Jingyu Li, Qile Guo, Yuan Liao, Chengxuan Yu, Danmei Jia, Jian Wu, Shibo He, Huanju Liu, Jun Ma, Kai Lei, Jiming Chen, Xiaoping Han, Guoji Guo
Journal: Nature Genetics (2022)
Emergence of Novel RNA-Editing Sites by Changes in the Binding Affinity of a Conserved PPR Protein
Authors: F Vanessa Loiacono, Dirk Walther, Stefanie Seeger, Wolfram Thiele, Ines Gerlach, Daniel Karcher, Mark Aurel Schöttler, Reimo Zoschke, Ralph Bock
Journal: Molecular Biology and Evolution (2022)

RNA editing converts cytidines to uridines in plant organellar transcripts. Editing typically restores codons for conserved amino acids. During evolution, specific C-to-U editing sites can be lost from some plant lineages by genomic C-to-T mutations. By contrast, the emergence of novel editing sites is less well documented. Editing sites are recognized by pentatricopeptide repeat (PPR) proteins with high specificity. RNA recognition by PPR proteins is partially predictable, but prediction is often inadequate for PPRs involved in RNA editing. Here we have characterized evolution and recognition of a recently gained editing site. We demonstrate that changes in the RNA recognition motifs that are not explainable with the current PPR code allow an ancient PPR protein, QED1, to uniquely target the ndhB-291 site in Brassicaceae. When expressed in tobacco, the Arabidopsis QED1 edits 33 high-confident off-target sites in chloroplasts and mitochondria causing a spectrum of mutant phenotypes. By manipulating the relative expression levels of QED1 and ndhB-291, we show that the target specificity of the PPR protein depends on the RNA:protein ratio. Finally, our data suggest that the low expression levels of PPR proteins are necessary to ensure the specificity of editing site selection and prevent deleterious off-target editing.
A potent antibiotic-loaded bone-cement implant against staphylococcal bone infections
Authors: Sumana Ghosh, Mau Sinha, Ritwik Samanta, Suresh Sadhasivam, Anamika Bhattacharyya, Ashis Nandy, Swamini Saini, Nupur Tandon, Himanshi Singh, Swati Gupta, Anjali Chauhan, Keerthi Kumar Aavula, Sneha Susan Varghese, Pujie Shi, Sudip Ghosh, Mukesh Kumar Garg, Tanmoy Saha, Aparna Padhye, Shamik Ghosh, Hae Lin Jang, Shiladitya Sengupta
Journal: Nature Biomedical Engineering (2022)
The Role of the Environment in Horizontal Gene Transfer
Authors: Hande Acar Kirit, Jonathan P Bollback, Mato Lagator
Journal: Molecular Biology and Evolution (2022)

Abstract Gene-by-environment interactions play a crucial role in horizontal gene transfer by affecting how the transferred genes alter host fitness. However, how the environment modulates the fitness effect of transferred genes has not been tested systematically in an experimental study. We adapted a high-throughput technique for obtaining very precise estimates of bacterial fitness, in order to measure the fitness effects of 44 orthologs transferred from Salmonella Typhimurium to Escherichia coli in six physiologically relevant environments. We found that the fitness effects of individual genes were highly dependent on the environment, while the distributions of fitness effects across genes were not, with all tested environments resulting in distributions of same shape and spread. Furthermore, the extent to which the fitness effects of a gene varied between environments depended on the average fitness effect of that gene across all environments, with nearly neutral and nearly lethal genes having more consistent fitness effects across all environments compared to deleterious genes. Put together, our results reveal the unpredictable nature of how environmental conditions impact the fitness effects of each individual gene. At the same time, distributions of fitness effects across environments exhibit consistent features, pointing to the generalizability of factors that shape horizontal gene transfer of orthologous genes.
Integrated analyses of brain and platelet omics reveal their common altered and driven molecules in Alzheimer's disease
Authors: Haitao Yu, Mengzhu Li, Qihang Pan, Yanchao Liu, Yao Zhang, Ting He, Huisheng Yang, Yue Xiao, Ying Weng, Yang Gao, Dan Ke, Gaoshang Chai, Jian‐Zhi Wang
Journal: MedComm (2022)

Abstract Platelets may serve as a perfect peripheral source for exploring diagnostic biomarkers for Alzheimer's disease (AD); however, the molecular linkage between platelet and the brain is missing. To find the common altered and driving molecules in both brain and the platelet, we performed an integrated analysis of our platelet omics and brain omics reported in the literature, and analyzed their correlations with AD‐specific pathology and cognitive impairment. By integrating the gene and protein expression profiles from 269 AD patients, we deduced 239 differentially expressed proteins (DEPs) appeared in both brain and the platelet, and 70.3% of them had consistent changes. Further analysis demonstrated that the altered brain and peripheral regulations were pinpointed into 10 imbalanced pathways. We also found that 117 DEPs, including ADAM10, were closely associated to the AD‐specific β‐amyloid and tau pathologies; and the changes of IDH3B and RTN1 had a potential diagnostic value for cognitive impairment analyzed by machine learning. Finally, we identified that HMOX2 and SERPINA3 could serve as driving molecules in neurodegeneration, and they were increased and decreased in AD patients, respectively. Together, this integrated brain and platelet omics provides a valuable resource for establishing efficient peripheral diagnostic biomarkers and potential therapeutic targets for AD.
Motor neurons use push-pull signals to direct vascular remodeling critical for their connectivity
Authors: Luis F. Martins, Ilaria Brambilla, Alessia Motta, Stefano de Pretis, Ganesh Parameshwar Bhat, Aurora Badaloni, Chiara Malpighi, Neal D. Amin, Fumiyasu Imai, Ramiro D. Almeida, Yutaka Yoshida, Samuel L. Pfaff, Dario Bonanomi
Journal: Neuron (2022)
Loss of NECTIN1 triggers melanoma dissemination upon local IGF1 depletion
Authors: Julien Ablain, Amira Al Mahi, Harriet Rothschild, Meera Prasad, Sophie Aires, Song Yang, Maxim E. Dokukin, Shuyun Xu, Michelle Dang, Igor Sokolov, Christine G. Lian, Leonard I. Zon
Journal: Nature Genetics (2022)

Abstract Cancer genetics has uncovered many tumor-suppressor and oncogenic pathways, but few alterations have revealed mechanisms involved in tumor spreading. Here, we examined the role of the third most significant chromosomal deletion in human melanoma that inactivates the adherens junction gene NECTIN1 in 55% of cases. We found that NECTIN1 loss stimulates melanoma cell migration in vitro and spreading in vivo in both zebrafish and human tumors specifically in response to decreased IGF1 signaling. In human melanoma biopsy specimens, adherens junctions were seen exclusively in areas with low IGF1 levels, but not in NECTIN1-deficient tumors. Our study establishes NECTIN1 as a major determinant of melanoma dissemination and uncovers a genetic control of the response to microenvironmental signals.
Collagen-binding peptides for the enhanced imaging, lubrication and regeneration of osteoarthritic articular cartilage
Authors: Chin-Yu Lin, Yung-Li Wang, Yu-Jen Chen, Chun-Te Ho, Yi-Hsuan Chi, Long Yi Chan, Guan-Wen Chen, Horng-Chaung Hsu, Dennis W. Hwang, Han-Chung Wu, Shih-Chieh Hung
Journal: Nature Biomedical Engineering (2022)
Meningeal dendritic cells drive neuropathic pain through elevation of the kynurenine metabolic pathway in mice
Authors: Alexandre G. Maganin, Guilherme R. Souza, Miriam D. Fonseca, Alexandre H. Lopes, Rafaela M. Guimarães, André Dagostin, Nerry T. Cecilio, Atlante S. Mendes, William A. Gonçalves, Conceição E.A. Silva, Francisco Isaac Fernandes Gomes, Lucas M. Mauriz Marques, Rangel L. Silva, Letícia M. Arruda, Denis A. Santana, Henrique Lemos, Lei Huang, Marcela Davoli-Ferreira, Danielle Santana-Coelho, Morena B. Sant’Anna, Ricardo Kusuda, Jhimmy Talbot, Gabriela Pacholczyk, Gabriela A. Buqui, Norberto P. Lopes, Jose C. Alves-Filho, Ricardo M. Leão, Jason C. O’Connor, Fernando Q. Cunha, Andrew Mellor, Thiago M. Cunha
Journal: Journal of Clinical Investigation (2022)

Neuropathic pain is one of the most important clinical consequences of injury to the somatosensory system. Nevertheless, the critical pathophysiological mechanisms involved in neuropathic pain development are poorly understood. In this study, we found that neuropathic pain is abrogated when the kynurenine metabolic pathway (KYNPATH) initiated by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is ablated pharmacologically or genetically. Mechanistically, it was found that IDO1-expressing dendritic cells (DCs) accumulated in the dorsal root leptomeninges and led to an increase in kynurenine levels in the spinal cord. In the spinal cord, kynurenine was metabolized by kynurenine-3-monooxygenase–expressing astrocytes into the pronociceptive metabolite 3-hydroxykynurenine. Ultimately, 3-hydroxyanthranilate 3,4-dioxygenase–derived quinolinic acid formed in the final step of the canonical KYNPATH was also involved in neuropathic pain development through the activation of the glutamatergic N-methyl-D-aspartate receptor. In conclusion, these data revealed a role for DCs driving neuropathic pain development through elevation of the KYNPATH. This paradigm offers potential new targets for drug development against this type of chronic pain.
Small molecule inhibitors targeting the cancers
Authors: Gui‐Hong Liu, Tao Chen, Xin Zhang, Xue‐Lei Ma, Hua‐Shan Shi
Journal: MedComm (2022)

Compared with traditional therapies, targeted therapy has merits in selectivity, efficacy, and tolerability. Small molecule inhibitors are one of the primary targeted therapies for cancer. Due to their advantages in a wide range of targets, convenient medication, and the ability to penetrate into the central nervous system, many efforts have been devoted to developing more small molecule inhibitors. To date, 88 small molecule inhibitors have been approved by the United States Food and Drug Administration to treat cancers. Despite remarkable progress, small molecule inhibitors in cancer treatment still face many obstacles, such as low response rate, short duration of response, toxicity, biomarkers, and resistance. To better promote the development of small molecule inhibitors targeting cancers, we comprehensively reviewed small molecule inhibitors involved in all the approved agents and pivotal drug candidates in clinical trials arranged by the signaling pathways and the classification of small molecule inhibitors. We discussed lessons learned from the development of these agents, the proper strategies to overcome resistance arising from different mechanisms, and combination therapies concerned with small molecule inhibitors. Through our review, we hoped to provide insights and perspectives for the research and development of small molecule inhibitors in cancer treatment.
The interferon-inducible protein viperin controls cancer metabolic reprogramming to enhance cancer progression
Authors: Kyung Mi Choi, Jeong Jin Kim, Jihye Yoo, Ku Sul Kim, Youngeun Gu, John Eom, Haengdueng Jeong, Kyungeun Kim, Ki Taek Nam, Young Soo Park, Joon-Yong Chung, Jun-Young Seo
Journal: Journal of Clinical Investigation (2022)

Metabolic reprogramming is an important cancer hallmark. However, the mechanisms driving metabolic phenotypes of cancer cells are unclear. Here, we show that the interferon-inducible (IFN-inducible) protein viperin drove metabolic alteration in cancer cells. Viperin expression was observed in various types of cancer and was inversely correlated with the survival rates of patients with gastric, lung, breast, renal, pancreatic, or brain cancer. By generating viperin knockdown or stably expressing cancer cells, we showed that viperin, but not a mutant lacking its iron-sulfur cluster–binding motif, increased lipogenesis and glycolysis via inhibition of fatty acid β-oxidation in cancer cells. In the tumor microenvironment, deficiency of fatty acids and oxygen as well as production of IFNs upregulated viperin expression via the PI3K/AKT/mTOR/HIF-1α and JAK/STAT pathways. Moreover, viperin was primarily expressed in cancer stem-like cells (CSCs) and functioned to promote metabolic reprogramming and enhance CSC properties, thereby facilitating tumor growth in xenograft mouse models. Collectively, our data indicate that viperin-mediated metabolic alteration drives the metabolic phenotype and progression of cancer.
Clinical and molecular response to tebentafusp in previously treated patients with metastatic uveal melanoma: a phase 2 trial
Authors: Richard D. Carvajal, Marcus O. Butler, Alexander N. Shoushtari, Jessica C. Hassel, Alexandra Ikeguchi, Leonel Hernandez-Aya, Paul Nathan, Omid Hamid, Josep M. Piulats, Matthew Rioth, Douglas B. Johnson, Jason J. Luke, Enrique Espinosa, Serge Leyvraz, Laura Collins, Howard M. Goodall, Koustubh Ranade, Chris Holland, Shaad E. Abdullah, Joseph J. Sacco, Takami Sato
Journal: Nature Medicine (2022)

Abstract In patients with previously treated metastatic uveal melanoma, the historical 1 year overall survival rate is 37% with a median overall survival of 7.8 months. We conducted a multicenter, single-arm, open-label phase 2 study of tebentafusp, a soluble T cell receptor bispecific (gp100×CD3), in 127 patients with treatment-refractory metastatic uveal melanoma (NCT02570308). The primary endpoint was the estimation of objective response rate based on RECIST (Response Evaluation Criteria in Solid Tumours) v1.1. Secondary objectives included safety, overall survival, progression-free survival and disease control rate. All patients had at least one treatment-related adverse event, with rash (87%), pyrexia (80%) and pruritus (67%) being the most common. Toxicity was mostly mild to moderate in severity but was greatly reduced in incidence and intensity after the initial three doses. Despite a low overall response rate of 5% (95% CI: 2–10%), the 1 year overall survival rate was 62% (95% CI: 53–70%) with a median overall survival of 16.8 months (95% CI: 12.9–21.3), suggesting benefit beyond traditional radiographic-based response criteria. In an exploratory analysis, early on-treatment reduction in circulating tumour DNA was strongly associated with overall survival, even in patients with radiographic progression. Our findings indicate that tebentafusp has promising clinical activity with an acceptable safety profile in patients with previously treated metastatic uveal melanoma, and data suggesting ctDNA as an early indicator of clinical benefit from tebentafusp need confirmation in a randomized trial.
Advisory Board and Contents
Authors: Jerry Madukwe, Danielle Loughlin, Fred Kop, Patrick Scheffmann, Michelle Arkin, Matthew Banks, Andrew Bate, Mary Bebawy, Jeffrey Benovic, Jacqueline Crawley, Debbie Hay, Stephanie Laszlo, Hunyady Magnus, Ingelman-Sundberg Michael, Kassiou Kum, Kum Khanna, Brian Kobilka, Jenny Lam, Michel Lazdunski, Fiona Marshall, Ruth Nussinov, Avner Schlessinger, Martina Schmidt, Harald Sitte, Rachel Tyndale, Ming-Wei Wang, Stephen Watson, Stephen Waxman, Matthew Webber
Journal: Trends in Pharmacological Sciences (2022)
Efficacy and safety of fluvoxamine for the treatment of COVID-19 patients: A systematic review and meta-analysis
Authors: Huzaifa Ahmad Cheema, Uzair Jafar, Asmaa Ahmed Elrashedy, Abia Shahid, Rehmat Ullah Awan, Muhammad Ehsan, Muhammad Ayyan, Syeda Sahra
Journal: Journal of Infection (2022)
Metabolism, Clinical and Experimental: seventy years young and growing
Authors: Stergios A Polyzos, Michael A Hill, Ghada El-Hajj Fuleihan, Luigi Gnudi, Young-Bum Kim, Susanna C Larsson, Hiroaki Masuzaki, Giuseppe Matarese, Despina Sanoudou, Manuel Tena-Sempere, Christos S Mantzoros
Journal: Metabolism (2022)